Study Rationale:
Alpha-synuclein is the primary component of Lewy bodies, the hallmark of Parkinson’s disease (PD). In particular, soluble aggregates of alpha-synuclein, also referred to as oligomers, have toxic effects. Because of their low abundance, a targeted oligomer-specific antibody-based treatment may be most effective. Antibodies, however, are very large and hard to pass into the brain. We have devised a gene therapy to ensure that the antibody is made where oligomers are known to occur (inside certain brain cells).
Hypothesis:
Our oligomer-specific antibody-based gene therapy can stop or slow disease progression in a Parkinson’s model.
Study Design:
We will generate smaller versions of the oligomer-specific antibody to make it better suitable for brain gene therapy. Then we will test our approach with the best candidates in cultured brain cells. Next, we will treat disease models that make excess alpha-synuclein in their substantia nigra, the brain region most affected in PD. These models develop motor function problems, and we aim to demonstrate that we can alleviate their PD symptoms with our once-only treatment.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Neutralizing alpha-synuclein oligomers in the brain is expected to have significant potential for treating PD. By demonstrating that we can impact disease progression in a Parkinson’s model with our antibody-based gene therapy would mean an important step toward developing treatment for PD patients.
Next Steps for Development:
If successful in this model, we would evaluate the treatment in an additional PD model before progressing to extensive toxicity testing and preparation for first-in-human studies, to be performed in carefully selected patients.